Registration Dossier

Administrative data

Description of key information

Magnesium is not acutely toxic via the oral, dermal, or inhalation route

Key value for chemical safety assessment

Acute toxicity: via oral route

Link to relevant study records
Reference
Endpoint:
acute toxicity: oral
Type of information:
migrated information: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Study period:
2009-11-10 to 2009-12-02
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: GLP guideline study
Qualifier:
according to guideline
Guideline:
OECD Guideline 423 (Acute Oral toxicity - Acute Toxic Class Method)
Version / remarks:
, 2001-12-17
Deviations:
no
GLP compliance:
yes (incl. QA statement)
Remarks:
signed 2009-04-06
Test type:
acute toxic class method
Limit test:
yes
Species:
rat
Strain:
Wistar
Sex:
female
Details on test animals or test system and environmental conditions:
TEST ANIMALS (The animals were derived from a controlled full barrier maintained breeding system (SPF). According to Art. 9.2, No.7 of the German Act of Animal Welfare the animals were bred for experimental purposes.)
- Source: Charles River, 97633 Sulzfeld, Germany
- Age at study initiation: 8 - 12 weeks old
- Weight at study initiation: Animals no. 1 - 3, step 1: 151 - 158 g; Animals no. 4 - 6, step 2: 161 -170 g
- Fasting period before study: Prior to administration food was withhel from the test animals for 16 to 19 hours (access to water was permitted). Food was provided again approximately 3 -4 hours post dosing.
- Housing: full-barrier in an air-conditioned room; The animals were kept in groups in IVC cages, type III H, polysulphone cages on Altromin saw fibre bedding (lot no. 06.06.09)
- Diet: Free access to Altromin 1324 maintenance diet for rats and mice (lot no. 1452)
- Water: Free access to tap water, sulphur acidified to a pH value of approx. 2.8 (drinking water, multicipal residue control, microbiological control at regular intervals.)
- Acclimation period: 6 days

ENVIRONMENTAL CONDITIONS
- Temperature: 22 +/- 3 °C
- Relative humidity: 55 +/- 10%
- Air changes: 10x / hour
- Photoperiod (hrs dark / hrs light): 12/12
No further information on the test animals was stated.
Route of administration:
oral: gavage
Vehicle:
water
Details on oral exposure:
VEHICLE
Aqua ad injection (sterile water, B. Braun Melsungen, lot no. 7494A191, expiry date: 11.2010)
- Justification for choice of vehicle: This vehicle was chosen due to its non-toxic characteristics.

DOSAGE PREPARATION: The test item was weighed out into a tared vial on a precision balance. A solution with the vehicle (Aqua ad injectionem (sterile water)) was prepared.
For all animals of the first and second step, 2 g of the test item were dissolved in the vehicle to gain a final volume of 5 mL and to achieve a dose of 2000 mg/kg body weight at a dose volume of 5 mL/kg body weight. The test item was administered at a dose volume of 5 mL/kg body weight.
The dose formulations were made shortly before each dosing occasion.
No further information on the oral exposure was stated.
Doses:
2000 mg/kg body weight
No. of animals per sex per dose:
3 female rats per step (Total: 6 female rats)
Control animals:
no
Details on study design:
- Duration of observation period following administration: All animals were observed for 14 days after dosing for general clinical signs morbidity and mortality.
- Frequency of observations and weighing: Prior to the administration a detailed clinical observation was made of all animals. Following the period of fasting the animals were weighed and the test item was administered. The animals were also weighed on days 8 and 15 after administration. A careful clinical examination was maade several times on the day of dosing (at least once during the first 30 minutes and with special attention given during the first 4 hoours post-dose). Thereafter, the animals were observed for clinical signs once daily until the end of the observation period. All abnormalities were recorded.
Cageside observations included changes in the skin and fur, eyes and mucous membranes. Also, respiratory, circulatory, autonomic and central nervous systems and somatomotor activity and behaviour pattern were examined. Particular attention was directed to observations of tremor, convulsions, salivation, diarrhoea, lethargy, sleep and coma.
- Necropsy of survivors performed: Yes
At the end of the observation period the animals were sacrificed with an overdosage of pentobarbital injected intraperitoneally (Narcoren®, manufacturer: Merial; lot no.: 193089; expiry date: 08.2012) at a dosage of approx. 8 mL/kg bw.
All animals were subjected to gross necropsy. All gross pathological changes were recorded.
No further information on the study design was stated.
Statistics:
No data
Sex:
female
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Based on:
test mat.
Remarks on result:
other: LD50 cut off value: 5000 mg/kg body weight
Mortality:
No mortality was observed.
Clinical signs:
No signs of toxicity were observed in any of the animals.
Body weight:
None of the animals showed weight loss during the observation period.
Gross pathology:
No special gross pathological changes were recorded for any animal.
Interpretation of results:
not classified
Remarks:
Migrated information Criteria used for interpretation of results: EU
Conclusions:
Under the conditions of the present study, a single oral application of the test item magnesium chloride hexahydrate to rats at a dose of 2000 mg/kg body weight was associated with no signs of toxicity or mortality.
The median lethal dose of magnesium chloride hexahydrate after a single oral administration to female rats, observed over a period of 14 days is :
LD50 cut off (rat): 5000 mg/kg body weight.
According to the Regulation (EC) No 1272/2008 and subsequent regulations, the test item is not acutely toxic via the oral route.
Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
discriminating dose
Value:
5 000 mg/kg bw

Acute toxicity: via inhalation route

Link to relevant study records
Reference
Endpoint:
acute toxicity: inhalation
Data waiving:
study scientifically not necessary / other information available
Justification for data waiving:
other:
Endpoint conclusion
Endpoint conclusion:
no study available

Acute toxicity: via dermal route

Link to relevant study records
Reference
Endpoint:
acute toxicity: dermal
Data waiving:
other justification
Justification for data waiving:
other:
Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

Acute toxicity, oral:

Read across from MgCl2 to Mg in acid media (oral toxicity):

The effect of acute toxicity of magnesium chloride hexahydrate and magnesium is based on the concentration of dissolved Mg2+and therefore on the solubility of each substance. The water solubility of magnesium (6.7 mg/L at 21°C/pH 10.8) is 106orders of magnitude lower than the water solubility of magnesium chloride hexahydrate (1 670 g/L at 20°C).Thus, read across to magnesium, based on worst case consideration, is justified.

Discussion:

There is one valid study available on acute oral toxicity, which was conducted with magnesium chloride hexahydrate. The LD50is > 2000 mg/kg bw. None of the 6 animals died, thus according to the OECD 423 the LD50could be set to 5000 mg/kg bw. Two additional published data are found during the literature search which results in LD50and LD100values, respectively wide above the threshold value for acute toxicity (up to 8100 mg/kg bw). However, these values should only be used as supportive information.

Nevertheless, some human case studies were reported and summarized in the SCF, 2001 document (please refer to the attached document in the endpoint summary of IUCLID section 7.2 “acute toxicity”):

“In 6 healthy volunteers about 4% of a 56.5 mmol oral dose of MgSO4(ca. 1,400 mg of Mg) given in 4 hours was enterally absorbed without inducing hypermagnesaemia. In the literature, only few cases of toxic hypermagnesaemia (>2.5 mmol/L) have been published, mostly owing to the (ab-) use of Mg as laxatives or antacids in single doses of >2,500 mg Mg. One published study reported maximal blood levels of 2 mmol Mg/L in 102 patients receiving ca. 9,200 mg of Mg daily (multiple doses, therapy of drug overdose) and Smilkstein et al. (1988) observed levels up to 2.5 mmol/L after daily doses of up to 360 mmol MgSO4(ca. 8,800 mg of Mg). Symptoms were hypotension, nausea and vomiting. Hypoventilation and respiratory depression were reported by Jones et al. (1986) and by Gren and Woolf (1989) in young women treated with Mg citrate (ca. 3,300 mg of Mg) for salicylate and tricyclic overdose; serum Mg levels were 5.7 and 4.0 mmol/L, respectively. Fung (1995) reported the case of a 69 years old multimorbid woman who took about ca. 24,000 mg Mg daily as an antacid; serum levels increased up to 6.7 mmol/L and caused hypoventilation. The patient recovered. Clark and Brown (1992) identified 12 elderly patients (70 ± 6 yr) among 19,761 hospital admissions with hypermagnesaemia (maximally 3.3 mmol/L); oral daily Mg doses (citrate, hydroxide) ranged between 2,000 to 6,300 mg of Mg. Hypotension was the most frequent clinical sequelae; 2 patients died due to refractory hypotension to which hypermagnesaemia may have contributed. As bowel disorders were present in most patients it is speculated that active ulcer disease, gastritis, colitis, etc. may enhance Mg absorption. Severely impaired renal function (inulin clearance <10 mL/min) is another risk factor (Aikawa, 1981; Randall et al., 1964). High age per se is however not a risk factor since Kinnunen and Salokannel (1987) did not observe hypermagnesaemia in 64 geriatric patients (mean age 81 years) receiving daily doses of 28 mmol Mg hydroxide (ca. 680 mg of Mg).”

 

In conclusion it can be stated that the LD50of magnesium could be set > 2000 mg/kg bw. Thus means that not classification and labeling is required in accordance to regulation (EC) 1272/2008.

Acute toxicity, dermal:

Acute toxicity testing via the dermal route is considered not to be scientifically justified.

However, following the HERAG guidance for metals and metal salts (see section 7.1.2 of the technical dossier, dermal absorption), a dermal absorption rate in the range of maximally 0.1-1.0 % can be anticipated. Dermal absorption in this order of magnitude is not considered to be “significant”.

Acute toxicity, inhalation:

An acute inhalation study in human volunteers is available, in which the potential of MgO to cause symptoms similar to that of metal fume fever is investigated. Due to the fact that magnesium metal is passivated on its surface by the formation of an oxide layer, and since in the case of fine powders this oxide layer will form a substantial part of the particle mass, and also because magnesium oxide and magnesium metal are of similarly low solubility (interpreted as a measure of similar bioavailability), read across from data on magnesium oxide to magnesium metal is considered justified without restriction.

However, the study conducted by Kuschner et al. was conducted with very fine MgO particles (98% < 2.5 µm), whereas the most representative magnesium powder placed on the market is characterised by a D90 of 86.1 µm (D50 53.1µm). Thus, commercial grades of magnesium powder are of much coarser nature than the MgO powder employed in the study by Kuschner et al. Thus, the alveolar deposition of MgO particles from the “Kuschner” study was obviously much higher than that of the much coarser commercial grades of magnesium powder. Therefore, any read across from MgO to Mg is intrinsically very conservative justified, and according to regulation (EC) 1907/2008 Annex XI point 1.1.3, any testing for acute inhalation toxicity testing is not required.

Justification for selection of acute toxicity – oral endpoint
Read-across information from a GLP guideline study with magnesium chloride hexahydrate as test item.

Justification for classification or non-classification

The available information indicates that magnesium is not acutely toxic or harmful. Therefore, classification of magnesium for acute toxicity is not warranted according to Regulation (EC) 1272/2008 and subsequent adaptations.

Specific target organ toxicant (STOT) – single exposure

The classification criteria according to Regulation (EC) 1272/2008 as specific target organ toxicant (STOT) – single exposure, oral, inhalation are not met since reversible or irreversible adverse health effects were not observed immediately or delayed after exposure.